Optimisation of pyruvate hyperpolarisation using SABRE by tuning the active magnetisation transfer catalyst

SABRE catalysts [Ir(H)2(η2-pyruvate)(sulfoxide)(NCH) transfer magnetisation from para-hydrogen to pyruvate yielding hyperpolarised 13C NMR signals enhanced by >2000-fold. Properties of the catalyst control efficiency.

. Variation of the [Ir(H) 2 (IMes)(η 2 -pyruvate)(L)] co-ligand, L S1.1: NMR spectra where L is 4-chlorobenzenemethanethiol S1.2: NMR spectra where L is Formaldehyde S1.3: NMR spectra where L is Triphenylphosphine S1.4: NMR spectra where L is Ethylisothiocyanate S1.5: NMR spectra where L is Thiophene S1.6: NMR spectra where L is Imidazole S1.7: X-ray crystallography of [Ir 2 (H) 4 (κ 2 -SCH 2 PhCl) 2 (IMes) 2 ] S1.8: X-ray crystallography of [Ir(H) 3  Samples were prepared containing [IrCl(COD)(IMes)] (5 mM) (where IMes = 1,3-bis(2,4,6-trimethyl-phenyl)imidazol-2-ylidene and COD = cis,cis-1,5-cyclooctadiene) with 6 equivalents of sodium pyruvate-1,2-[ 13 C2] and 4 equivalents of the specified co-ligand (L) in 0.6 mL of methanol-d4 unless otherwise stated in a 5 mm NMR tube that was fitted with a J. Young's tap. The co-ligands used in this study are 4-chlorobenzenemethanethiol, formaldehyde, triphenylphosphine, ethylisothiocyanate, thiophene, imidazole, dimethylsulfoxide (DMSO) (I), phenylmethylsulfoxide (II), chlorophenylmethylsulfoxide (III), vinylsulfoxide (IV), diphenylsulfoxide (V), dibenzylsulfoxide (VI), dibutylsulfoxide (VII), tetramethylene sulfoxide (VIII), methionine sulfoxide (IX) and Fmoc-L-methionine sulfoxide (X) which were all purchased from Sigma Aldrich and used without further purification. Unless otherwise stated, the iridium catalyst used was [IrCl(COD)(IMes)]. The iridium precatalysts used in this work were synthesized in our laboratory according to literature procedures. 1 The solutions were subsequently degassed by two freeze-pump-thaw cycles before 3 bar H2 was added. These samples were then analysed by SABRE-NMR methods. Typical NMR spectra are shown in Figures S1-S24. Some of the data ( Figure S9-S20) uses sodium pyruvate-1-[ 13 C] as the reagent due to lower reagent cost. S1.1: NMR spectra where L is 4-chlorobenzenemethanethiol                   and 4 equivalents of 4-chlorobenzenemethanethiol in 0.6 mL of methanol-d4 with 3 bar H2 at 278 K for a period of several months. A suitable crystal was selected and mounted on an Oxford Diffraction SuperNova X-ray diffractometer. The crystal was kept at 110 K during data collection. Diffractometer control, data collection, initial unit cell determination, frame integration and unit-cell refinement was carried out with "CrysAlisPro". 2 Face-indexed absorption corrections were applied using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Using Olex2, 3 the structure was solved with the ShelXT 4 structure solution program using Intrinsic Phasing and refined with the ShelXL 5 refinement package using Least Squares minimisation. X-ray crystal structures were deposited with the CCDC (deposition number 1957542-1957543) The crystal of [Ir2(H)4(κ 2 -SCH2PhCl)2(IMes)2] showed evidence of minor twinning with two residual density peaks close to the iridium atoms. This could not be resolved using either merohedral or non-merohedral twinning methods. One of the 4-chlorobenzyl groups was disordered and modelled in two positions with refined occupancies of 0.803:0.197(10). Pairs of disordered carbons were constrained to have the same ADP (e.g. C43, & C43a, C44 & C44a etc.). The S-CH2 bond-lengths were restrained to be equal as were the CH2-C(ipso) bond-lengths and the C-Cl bond-lengths. The phenyl ring of the minor form was constrained to be a regular hexagon with a C-C bond length of 1.39 angstroms. For the minor form the CH2-C(ortho) distances were restrained to be equal as were the C(meta)-Cl distances. The hydrides were initially located by difference map, the Ir-H bond-length was then adjusted to be 1.65 angstroms and then the location fixed to ride on the iridium.

S1.8: X-ray crystallography of [Ir(H) 3 (PPh 3 ) 3 ]
Crystals were grown by leaving a sample containing 2 mg [IrCl(COD)(IMes)] (where IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene and COD = cis,cis-1,5-cyclooctadiene) with 6 equivalents of sodium pyruvate-1,2-[ 13 C2] and 4 equivalents of triphenylphosphine in 0.6 mL of methanol-d4 with 3 bar H2 at 278 K for a period of several months. A suitable crystal was selected and X-ray diffraction data was collected and solved as described in Section S1.7. The asymmetric unit contained a partial methanol whose occupancy refined to 0.283(5).    The concentration of methylphenylsulfoxide II was varied to determine its effect on pyruvate enhancement. The relative 13 C NMR signal gains for bound and free pyruvate, in addition to the hydride ligand signal enhancements for its 3b derivative across a range of concentrations, are presented in Figure 3  SUPPORTING INFORMATION S16

S2.2: Effect of changing the chloride concentration
Solutions of 2 mg 1a, 10 equivalents of sulfoxide I and 5 equivalents of sodium pyruvate-1,2-[ 13 C2] in 0.6 mL methanol-d4 containing 0, 1, 3 or 5 equivalents of NaCl in 5 μL of D2O were prepared. These four solutions were activated with 3 bar H2 and their 13 C2 pyruvate enhancement monitored as a function of reaction time. Signal enhancements for this data were calculated by reference to a thermal 128 scan 13 C NMR spectrum of the same sample and were consistent with those calculated by reference to a more concentrated sodium pyruvate-1,2-[ 13 C2] thermal sample as outlined in Shchepin et al.  S3.2: Hyperpolarised 13 C and 1 H spectra using sulfoxide IX Figure Figure S36: Hyperpolarised 1 scan 13 C NMR spectrum recorded at 298 K (below) resulting from shaking a sample of [IrCl(COD)(IMes)], sodium pyruvate-1,2-[ 13 C2] and sulfoxide X in methanol-d4 with 3 bar p-H2 for 10 seconds in a mu metal shield with the corresponding thermal measurement (64 scans) displayed above.
S4. Optimisation of 13 C 2 Pyruvate signal enhancement S4.1: Effect of shaking time and p-H 2 pressure Figure S37: a) Average hyperpolarised 13 C pyruvate signal enhancement as a function of hydrogen pressure (1a with 2 eq phenylmethylsulfoxide, 3 bar p-H2 and 10 second shaking). Hyperpolarised b) 13 C pyruvate and 1 H hydride responses seen for 3b as a function of shaking time recorded on the same sample (3 bar Figure S38: a) Average hyperpolarised 13 C pyruvate signal enhancement as a function of hydrogen pressure (1a-d24 with 10 eq phenylmethylsulfoxide, 3 bar p-H2 and 10 second shaking). Hyperpolarised b) 13 C pyruvate and 1 H hydride responses seen for 3b as a function of shaking time recorded on the same sample (3 bar).
S4.2: Effect of pyruvate concentration Figure S39: Average hyperpolarised 13 C pyruvate signal enhancement and hypeprolarised hydride signal intensity of 3b as a function of pyruvate concentration relative to iridium for a sample containing 1a with 10 eq phenylmethylsulfoxide and 3 bar p-H2 after 10 seconds of shaking.